U.S. Pat. No. 5,134,127 (the '127 patent) relates to sulfoalkyl ether cyclodextrin (SAE-CD) derivatives. The SAE-CD derivatives are proposed to be used as solubilizing agents for poorly water soluble or water insoluble drugs in various pharmaceutical dosage forms.
Cyclodextrin/drug complexes are typically formed prior to their use in pharmaceutical formulations. The '127 patent relates to compositions and formulations containing a drug complexed to a SAE-CD derivative to form clathrate/drug complexes or inclusion complexes thereof. Pharmaceutical formulations contemplated therein relate to those that include the clathrate complex and a pharmaceutically acceptable carrier.
The SAE-CD/drug clathrate complexes are prepared separately prior to placement in a desired pharmaceutical formulation. Processes to prepare such formulations include steps that require much process monitoring and control and as such may complicate the formulation process. In the pharmaceutical industry, simplified processes are preferred over complex ones, and, with regard to cyclodextrin-containing and, specifically, SAE-CD-containing compositions, a need continues to exist for simplified compositions and processes for their preparation.
Efforts have been made to formulate cyclodextrins with poorly water soluble drugs together as physical mixtures and as inclusion complexes. Muranushi et al. (1988) compared the dissolution profiles for neat benexate, benexate/cyclodextrin physical mixture and benexate-cyclodextrin complex. They reported the significantly increased solubility of benexate when prepared in the complexed vs physyical mixture or neat forms.
Similar results were reported by J. J. Torres-Labandeira et al. (1994) wherein the bioavailability of glibornuride-.beta.-cyclodextrin complex was found to be two to three fold better than that of the glibornuride/.beta.-cyclodextrin physical mixture. D. Peri et al. (1994) also reported that the drug-.beta.-cyclodextrin complex showed improved dissolution over the physical mixture or free drug for tolnaftate. When naproxen and .beta.-cyclodextrin were tested, the respective inclusion complex was found to have a six to nine fold increased solubility at five minutes over that of the physical mixture. (Otero-Espinar et al., 1991)
Further evidence that the drug-.beta.-cyclodextrin inclusion complex possesses a significantly improved dissolution profile than the corresponding physical mixture was reported by Lin et al. (1989) when .beta.-cyclodextrin complexes and physical mixtures of acetaminophen, indomethacin, piroxicam and warfarin were tested. Esclusa-Diaz et al. (1996) also reported that the ketoconazole-.beta.-cyclodextrin complex had a significantly better solubility than the corresponding physical mixture.
U.S. Pat. No. 4,946,686 to McClelland et al. discloses but does not exemplify another application of drug/cyclodextrin physical mixtures. This composition was designed solely for controlled release of a drug wherein solubility modulating units were present as slow release particles dispersed throughout a mixture of drug excipients. All of the components were then surrounded by a microporous water insoluble wall.
Thus, the art generally teaches that a drug-cyclodextrin complex will have significantly better solubility, dissolution profile and bioavailability than its respective physical mixture. A need continues to exist in the pharmaceutical arts for a pharmaceutical formulation containing a drug/cyclodextrin physical mixture that possesses a dissolution profile, bioavailability and solubility approximately those characteristic of the respective drug-cyclodextrin complex.